1. Field of the Invention
This invention relates to the preparation of apical sodium co-dependent bile acid transporter (ASBT) inhibitors and more particularly to the preparation of benzothiepine ASBT inhibitors. This invention especially relates to methods of preparing tetrahydrobenzothiepine oxide ASBT inhibitors.
2. Description of Related Art
It is well established that agents which inhibit the transport of bile acids across the tissue of the ileum can also cause a decrease in the levels of cholesterol in blood serum. Stedronski, in xe2x80x9cInteraction of bile acids and cholesterol with nonsystemic agents having hypocholesterolemic properties,xe2x80x9d Biochimica et Biophysica Acta, 1210 (1994) 255-287 discusses biochemistry, physiology, and known active agents surrounding bile acids and cholesterol. Bile acids are actively transported across the tissue of the ileum by an apical sodium co-dependent bile acid transporter (ASBT), alternatively known as an ileal bile acid transporter (IBAT).
A class of ASBT-inhibiting compounds that was recently discovered to be useful for influencing the level of blood serum cholesterol comprises tetrahydrobenzothiepine oxides (THBO compounds, PCT Patent Application No. WO 96/08484). Further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 97/33882. Additional THBO compounds useful as ASBT inhibitors are described in U.S. Pat. No. 5,994,391. Still further THBO compounds useful as ASBT inhibitors are described in PCT Patent Application No. WO 99/64409. Included in the THBO class are tetrahydrobenzothiepine-1-oxides and tetrahydrobenzothiepine-1,1-dioxides. THBO compounds possess chemical structures in which a phenyl ring is fused to a seven-member ring.
Published methods for the preparation of THBO compounds include the synthesis through an aromatic sulfone aldehyde intermediate. For example 1-(2,2-dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene (9) was cyclized with potassium t-butoxide to form tetrahydrobenzothiepine-1,1-dioxide (syn-24) as shown in Eq. 1. 
Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acid chloride with anisole in the presence of aluminum trichloride to produce a chlorobenzophenone compound; the chlorobenzophenone compound was reduced in the presence of trifluoromethanesulfonic acid and triethylsilane to produce a chlorodiphenylmethane compound; the chlorodiphenylmethane compound was treated with lithium sulfide and 2,2-dibutyl-3-(methanesulfonato)propanal to produce 1-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene (40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29. The first step of that method of preparing compound 29 requires the use of a corrosive and reactive carboxylic acid chloride that was prepared by the reaction of the corresponding carboxylic acid with phosphorus pentachloride.
Phosphorus pentachloride readily hydrolyzes to produce volatile and hazardous hydrogen chloride. The reaction of 2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide and the chlorodiphenylmethane compound required the intermediacy of a cyclic tin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal. The tin compound is expensive and creates a toxic waste stream.
In WO 97/33882 compound syn-24 was dealkylated using boron tribromide to produce the phenol compound 28. Boron tribromide is a corrosive and hazardous material that generates hydrogen bromide gas and requires special handling. Upon hydrolysis, boron tribromide also produces borate salts that are costly and time-consuming to separate and dispose of. 
An alternative method of preparing THBO compounds was described in WO 97/33882, wherein a 1,3-propanediol was reacted with thionyl chloride to form a cyclic sulfite compound. The cyclic sulfite compound was oxidized to produce a cyclic sulfate compound. The cyclic sulfate was condensed with a 2-methylthiophenol that had been deprotonated with sodium hydride. The product of the condensation was a (2-methylphenyl) (3xe2x80x2-hydroxypropyl)thioether compound. The thioether compound was oxidized to form an thioether aldehyde compound. The thioether aldehyde compound was further oxidized to form an aldehyde sulfone compound which in turn was cyclized in the presence of potassium t-butoxide to form a 4-hydroxytetrahydrobenzothiepine 1,1-dioxide compound. This cyclic sulfate route to THBO compounds requires an expensive catalyst. Additionally it requires the use of SOCl2, which in turn requires special equipment to handle.
PCT Patent Application No. WO 97/33882 describes a method by which the phenol compound 28 was reacted at its phenol hydroxyl group to attach a variety of functional groups to the molecule, such as a quaternary ammonium group. For example, (4R,5R)-28 was reacted with 1,4-bis(chloromethyl)benzene (?,??xe2x80x2-dichloro-p-xylene) to produce the chloromethyl benzyl ether (4R,5R)-27. Compound (4R,5R)-27 was treated with diazabicyclo[2.2.2]octane (DABCO) to produce (4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride (41). This method suffers from low yields because of a propensity for two molecules of compound (4R,5R)-28 to react with one molecule of 1,4-bis(chloromethyl)benzene to form a bis(benzothiepine) adduct. Once the bis-adduct forms, the reactive chloromethyl group of compound (4R,5R)-27 is not available to react with an amine to form the quaternary ammonium product. 
A method of preparing enantiomerically enriched tetrahydrobenzothiepine oxides is described in PCT Patent Application No. WO 99/32478. In that method, an aryl-3-hydroxypropylsulfide compound was oxidized with an asymmetric oxidizing agent, for example (1R)-(xe2x88x92)-(8,9-dichloro-10-camphorsulfonyl)oxaziridine, to yield a chiral aryl-3-hydroxypropylsulfoxide. Reaction of the aryl-3-hydroxypropylsulfoxide with an oxidizing agent such as sulfur trioxide pyridine complex yielded an aryl-3-propanalsulfoxide. The aryl-3-propanalsulfoxide was cyclized with a base such as potassium t-butoxide to enantioselectively produce a tetrahydrobenzothiepine-1-oxide. The tetrahydrobenzothiepine-1-oxide was further oxidized to produce a tetrahydrobenzothiepine-1,1-dioxide. Although this method could produce tetrahydrobenzothiepine-1,1-dioxide compounds of high enantiomeric purity, it requires the use of an expensive asymmetric oxidizing agent.
Some 5-amidobenzothiepine compounds and methods to make them are described in PCT Patent Application Number WO 92/18462.
In Synlett, 9, 943-944(1995) 2-bromophenyl 3-benzoyloxy-1-buten-4-yl sulfone was treated with tributyl tin hydride and AIBN to produce 3-benzoyloxytetrahydrobenzothiepine-1,1-dioxide.
The ongoing work in the area of tetrahydrobenzothiepine synthesis and the utility of 4-hydroxy-5-phenyltetrahydrobenzothiepine-1,1-dioxide compounds as cholesterol-lowering therapeutics point to the continuing need for economical and practical methods to prepare these compounds.
We now report a novel method for preparing tetrahydrobenzothiepine compounds. Among the several embodiments of the present invention may be noted the provision of an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.
Briefly, therefore, the present invention is directed to a method for the preparation of a benzylammonium compound having the structure of Formula 60
wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula 61
under derivatization conditions to form a derivatized benzyl ether compound having the structure of Formula 62
and contacting the derivatized benzyl ether compound with an amine having the structure of Formula 42
under amination conditions thereby producing the benzylammonium compound or a derivative thereof, wherein:
R1 and R2 independently are C1 to about C20 hydrocarbyl;
R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5Axe2x88x92, SR3, S(O)R3, SO2R3, SO3R3, oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5Axe2x88x92, S+R3R4Axe2x88x92, and C(O)OM;
R23 and R24 are independently selected from the substituents constituting R3 and M;
n is a number from 0 to 4;
Axe2x88x92 is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation; and
X is a nucleophilic substitution leaving group.
The present invention is also directed to a method for the preparation of a benzylammonium compound having the structure of Formula 1
wherein the method comprises treating a benzyl alcohol ether compound having the structure of Formula 6
under derivatization conditions to form a derivatized benzyl ether compound having the structure of Formula 2
and contacting the derivatized benzyl ether compound with an amine having the structure of Formula 42: 
under amination conditions thereby producing the benzylammonium compound or a derivative thereof, wherein R1, R2, R3, R4, R5, and X are defined above.
The invention is further directed to a method for the preparation of a benzylammonium compound having the structure of Formula 1 wherein the method comprises the steps of: treating a protected phenol compound having the structure of Formula 14
with a substituted benzoyl compound having the structure of Formula 15
under acylation conditions to produce a substituted benzophenone compound having the structure of Formula 13
reducing the substituted benzophenone compound to produce a substituted diphenyl methane compound having the structure of Formula 11
coupling the substituted diphenyl methane compound with a substituted propionaldehyde compound having the structure of Formula 12
in the presence of a source of sulfur to form a nitro sulfide aldehyde compound having the structure of Formula 10
oxidizing the nitro sulfide aldehyde compound to form a nitro sulfone aldehyde compound having the structure of Formula 9
reductively alkylating the nitro sulfone aldehyde compound to form an amino sulfone aldehyde compound having the structure of Formula 8
treating the amino sulfone aldehyde compound under cyclization conditions to form protected phenol compound having the structure of Formula 7
deprotecting the protected phenol compound to form a phenol compound having the structure of Formula 4
coupling the phenol compound with a substituted xylene having the structure of Formula 5
under substitution conditions to produce a benzyl alcohol ether compound having the structure of Formula 6 treating the benzyl alcohol ether compound under derivatization conditions to produce a derivatized benzyl ether compound having the structure of Formula 2; and treating the derivatized benzyl ether compound with an amine having the structure of Formula 42 under amination conditions to produce the benzylammonium compound 1; wherein: R1, R2, R3, R4, and R5 are as defined above; R6 is a protecting group, X and X4 independently are nucleophilic substitution leaving groups, X2 is selected from the group consisting of chloro, bromo, iodo, methanesulfonato, toluenesulfonato, benzenesulfonato, and trifluoromethanesulfonato; X3 is an aromatic substitution leaving group; and X5 is selected from the group consisting of hydroxy and halo.
The present invention is also directed to a method for the preparation of a benzylammonium compound having the structure of Formula 1 wherein the method comprises a step in which an acetal compound having the structure of Formula 18
is thermolyzed to form an alkenyl sulfone aldehyde compound having the structure of Formula 16
wherein R1 and R6 are as defined above; R7 is selected from the group consisting of H and C1 to about C17 hydrocarbyl; and R13 is selected from the group consisting of H and C1 to about C20 hydrocarbyl.
In another embodiment, the present invention is directed to a method of treating a diastereomer of a tetrahydrobenzothiepine compound having the structure of Formula 22
wherein Formula 22 comprises a (4,5)-diastereomer selected from the group consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a (4R,5S) diastereomer, and a (4S,5R) diastereomer, to produce a mixture comprising the (4S,5S) diastereomer and the (4R,5R) diastereomer, wherein the method comprises contacting a base with a feedstock composition comprising the diastereomer of the tetrahydrobenzothiepine compound, thereby producing a mixture of diastereomers of the tetrahydrobenzothiepine compound; and wherein:
R8 is selected from the group consisting of H, hydrocarbyl, heterocycle, ((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl, ((heterocycloalkyl)alkylaryl)alkyl, ((quaternary heterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl,
wherein hydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl optionally have one or more carbons replaced by a moiety selected from the group consisting of O, NR3, N+R3R4Axe2x88x92, S, SO, SO2, S+R3Axe2x88x92, PR3, P+R3R4Axe2x88x92, P(O)R3, phenylene, carbohydrate, amino acid, peptide, and polypeptide, and
R8 is optionally substituted with one or more moieties selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5Axe2x88x92, SR3, S(O)R3, SO2R3, SO3R3, oxo, CO2R3, CN, halogen, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5Axe2x88x92, S+R3R4Axe2x88x92, and C(O)OM;
R1, R2, R3, R4, R5, R9, R23 and R24, n, Axe2x88x92, and M are as defined above;
X7 is S, NH, or O; and
x is 1 or 2.
In yet another embodiment, the present invention is directed to a method of treating a diastereomer of a tetrahydrobenzothiepine compound having the structure of Formula (22), wherein the method comprises treating the diastereomer of the tetrahydrobenzothiepine compound under elimination conditions to produce a dihydrobenzothiepine compound having the structure of Formula 23
and oxidizing the dihydrobenzothiepine compound to produce the mixture of diastereomers, wherein:
R1, R2, R8, R9, X7, and n are as defined above; and
x is 0, 1, or 2.
Another embodiment of the present invention is directed to a method for the preparation of a substituted propionaldehyde compound having the structure of Formula 12 wherein the method comprises oxidizing a substituted propanol compound having the structure of Formula 35
wherein R1 and R2 are as defined above, and X4 is a nucleophilic substitution leaving group.
In another embodiment, the present invention is directed toward a compound having the structure of Formula (2) wherein R1 and R2 independently are C1 to about C20 hydrocarbyl and X is selected from the group consisting of Br, I, and a nucleophilic substitution leaving group covalently bonded to the compound via an oxygen atom.
In another embodiment, the present invention provides a crystalline form of a tetrahydrobenzothiepine compound having the structure of Formula 71
or an enantiomer thereof wherein the crystalline form has a melting point or a decomposition point of about 278xc2x0 C. to about 285xc2x0 C.
Another embodiment of the present invention provides a crystalline form of a tetrahydrobenzothiepine compound wherein the tetrahydrobenzothiepine compound has the structure of Formula 71 and which after a sample of the crystalline form is dried at essentially 0% relative humidity at about 25xc2x0 C. under a purge of essentially dry nitrogen until the sample exhibits essentially no weight change as a function of time, the sample gains less than 1% of its own weight when equilibrated under about 80% relative humidity air at about 25xc2x0 C. Preferably the crystal form of the present invention comprises a (4R,5R)-enantiomer of compound 71.
Still another embodiment of the present invention provides a crystalline form of a tetrahydrobenzothiepine compound wherein the tetrahydrobenzothiepine compound has the structure of Formula 71 or an enantiomer thereof and wherein the crystalline form is produced by crystallizing the tetrahydrobenzothiepine compound from a solvent comprising methyl ethyl ketone. Preferably the crystal form of the present invention comprises a (4R,5R)-enantiomer of compound 71.
In another embodiment, the present invention provides a method for the preparation of a crystalline form of a tetrahydrobenzothiepine compound having the structure of Formula 63
wherein the method comprises crystallizing the tetrahydrobenzothiepine compound from a solvent comprising a ketone (for example methyl ethyl ketone or acetone, preferably methyl ethyl ketone), and wherein R1, R2, R3, R4, R5, R9, and n are defined above. In Formula 63 Qxe2x88x92 is a pharmaceutically acceptable anion.
In another embodiment, the present invention provides a method for the preparation of a product crystal form of a tetrahydrobenzothiepine compound having the compound structure of Formula 41 wherein the product crystal form has a melting point or a decomposition point of about 278xc2x0 C. to about 285xc2x0 C., wherein the method comprises applying heat to an initial crystal form of the tetrahydrobenzothiepine compound wherein the initial crystal form has a melting point or a decomposition point of about 220xc2x0 C. to about 235xc2x0 C., thereby forming the product crystal form.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. However, it should be understood that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.